Serotonergic circuits in the brain have long been known to play an important role in regulating energy balance. Despite extensive study of serotonin and its receptors, we have an incomplete understanding of how and when serotonin impacts energy balance. While serotonin generally seems to suppress feeding behavior, in part through activation of its receptor 5HT2CR, we have recently found that genetic and pharmacological inactivation of this receptor reduces the refeeding that occurs after an overnight fast. This finding suggests that impact of 5HT2CR signaling on feeding under ad libitum feeding conditions differs from that during conditions of energy deprivation. Here, we propose to investigate the mechanism behind this unanticipated phenomenon. First, we will determine whether inactivation of 5HT2CR alters behavioral and physiological responses to fasting conditions. To this end, we will carefully monitor differences in the metabolic and hormonal changes that accompany an overnight fast. Secondly, we will explore the possibility that 5HT2CR signaling may be required for normal behavioral responsiveness to fasting-associated hormonal alterations. Finally, we will test the hypothesis that these 5HT2CR effects are mediated by a subpopulation of receptors expressed within the hypothalamic arcuate nucleus. We will employ a transgenic system recently developed in our lab to eliminate 5HT2C receptors specifically in neurons expressing proopiomelanocortin (POMC). Taken together, these experiments should increase the understanding of the complex regulation of energy balance by serotonin. PUBLIC HEALTH RELEVANCE: Despite a long history of study of neuronal serotonin, much remains to be learned about the mechanisms through which it impacts energy balance. Recent advances in genetic and pharmacological tools now make it possible to investigate this system with increased precision and sensitivity. This proposal seeks to explore the role of serotonin in an important aspect of energy balance, behavioral responsiveness to energy depletion. This knowledge could facilitate the development of therapies to combat obesity, and other metabolic disorders, as well as the prevention of adverse metabolic effects of psychoactive drugs.